Inhibition of SIRT1/2 upregulates HSPA5 acetylation and induces pro-survival autophagy via ATF4-DDIT4-mTORC1 axis in human lung cancer cells
Inhibition of SIRT1/2 upregulates HSPA5 acetylation and induces pro-survival autophagy via ATF4-DDIT4-mTORC1 axis in human lung cancer cells
复制标题
抑制 SIRT1/2 可上调 HSPA5 乙酰化并通过 ATF4-DDIT4-mTORC1 轴在人肺癌细胞中诱导促生存自噬
DOI：
10.1007/s10495-019-01559-3
复制
发表时间：
2019-10-01
期刊：
影响因子：
7.2
通讯作者：
Su, Ling
中科院分区：
文献类型：
--
作者：
Mu, Ning;Lei, Yuanjiu;Su, Ling
Sirtuins已成为一类有前途的新型抗癌药物靶点。SIRT 1和SIRT 2的抑制可诱导癌细胞凋亡，并且它们在调节自噬方面发挥多方面的作用。在本研究中，我们发现salermide，一种SIRT 1/2特异性抑制剂或小干扰RNA（siRNA）阻断SIRT 1/2表达可以诱导人NSCLC细胞自噬。此外，SIRT 1/2抑制增加ATF 4和DDIT 4的表达水平，并下调mTORC 1的两个下游分子p-RPS 6 KB 1和p-EIF 4 EBP 1。此外，ATF 4或DDIT 4敲除减弱了萨勒米德诱导的自噬，表明SIRT 1/2抑制通过ATF 4-DDIT 4-mTORC 1轴诱导自噬。在机制上，SIRT 1/2抑制导致HSPA 5乙酰化和从EIF 2AK 3解离，导致ER应激反应，随后上调ATF 4和DDIT 4，触发自噬。自噬基因ATG 5在肺癌细胞中的沉默导致SIRT 1/2抑制诱导的凋亡性细胞死亡增加。我们的数据显示，SIRT 1/2的抑制通过HSPA 5的乙酰化和随后的ATF 4和DDIT 4的激活来诱导促存活自噬，以抑制NSCLC细胞中的mTOR信号传导途径。这些发现表明，SIRT 1/2抑制剂和药理学自噬抑制剂的组合治疗是癌症治疗的有效治疗策略。
Sirtuins have emerged as a promising novel class of anti-cancer drug targets. Inhibition of SIRT1 and SIRT2 induces apoptosis in cancer cells and they play multifaceted roles in regulating autophagy. In the present study, we found that salermide, a SIRT1/2-specific inhibitor or small interfering RNAs (siRNAs) to block SIRT1/2 expression could induce autophagy in human NSCLC cells. Moreover, SIRT1/2 inhibition increased the expression levels of ATF4 and DDIT4 and downregulated p-RPS6KB1 and p-EIF4EBP1, two downstream molecules of mTORC1. Moreover, ATF4 or DDIT4 knockdown attenuated salermide-induced autophagy, suggesting that SIRT1/2 inhibition induced autophagy through the ATF4-DDIT4-mTORC1 axis. Mechanistically, SIRT1/2 inhibition led to HSPA5 acetylation and dissociation from EIF2AK3, leading to ER stress response and followed by upregulation of ATF4 and DDIT4, triggering autophagy. Silencing of the autophagic geneATG5in lung cancer cells resulted in increased apoptotic cell death induced by SIRT1/2 inhibition. Our data show that inhibition of SIRT1/2 induces pro-survival autophagy via acetylation of HSPA5 and subsequent activation of ATF4 and DDIT4 to inhibit the mTOR signaling pathway in NSCLC cells. These findings suggest that combinatorial treatment with SIRT1/2 inhibitors and pharmacological autophagy inhibitors is an effective therapeutic strategy for cancer therapy.